BKM120,944396-07-0,IC-0230954

BKM120(NVP-BKM120, Buparlisib) is a selective PI3K inhibitor of p110α/β/δ/γ with IC50 of 52 nM/166 nM/116 nM/262 nM, respectively.
The intracellular phosphatidylinositol-3-kinase(PI3K) pathway regulates cellular functions incuding cell proliferation, growth, survival, apoptosis, protein synthesis, and glucose metabolism. BKM120, a biologic characterization of the 2-morpholino pyrimidine derivative, is a pan-PI3K inhibitor.
In vitro: NVP-BKM120 inhibits all four class I PI3K isoforms in biochemical assays with at least 50-fold selectivity against other protein kinases. NVP-BKM120 is also active against the most common somatic PI3Ka mutations but does not significantly inhibit the related class III (Vps34) and class IV (mTOR, DNA-PK) PI3K kinases. Consistent with its mechanism of action, NVP-BKM120 decreases the cellular p-Akt levels in mechanistic models and relevant tumor cell lines. In a panel of 353 cell lines test, NVP-BKM120 showed preferential inhibition of tumor cells with PIK3CA mutations, rather than either KRAS or PTEN mutant models [1].
In vivo: NVP-BKM120 shows dose-dependent in vivo pharmacodynamic activity as measured by significant inhibition of p-Akt and tumor growth inhibition in mechanistic xenograft models. In addition, NVP-BKM120 behaves synergistically when combined with either targeted agents such as MEK or HER2 inhibitors or with cytotoxic agents such as docetaxel or temozolomide [1].
Clinical trial: A phase I dose-escalation study investigated the maximum-tolerated dose (MTD), safety, preliminary activity, PK, and PD of BKM120. This study demonstrates feasibility and proof-of-concept of class I PI3K inhibition in cancer patients. BKM120 at the MTD of 100 mg d-1 is safe and well tolerated, with a good PK profile, clear evidence of target inhibition, and preliminary antitumor activity [2